Protein Interacting with C-Kinase (PICK1) is a multifunctional scaffold protein that interacts with many proteins in neurons and glial cells. We recently reported that PICK1 binds directly to the D-serine synthesizing enzyme, serine racemase (SR). Knockdown expression of PICK1 decreased levels of D-serine from SR in cell cultures. We published that decreased levels of D-serine were observed in neonatal forebrains in PICK1 knockout (PICK1 KO), consistent with the observation from cell biology. Several recent studies have suggested roles for D-serine in mental disturbances associated with cortical circuitry, including schizophrenia. To our knowledge, however, roles for PICK1 have largely been studied in the context of synaptic plasticity, mainly by using slices from the cerebellum and hippocampus. Therefore, in this proposed study, we will examine PICK1 knockout mice in behavioral assays and electrophysiological approaches and focus on the impact of the protein on D- serine disposition and brain functions, especially those associated with cortical circuitry. In our preliminary studies, we obtained (1) decreased levels of D-serine in the forebrain during the neonatal period, but not in the adulthood;(2) several behavioral deficits in adulthood, which includes those in spatial working memory and prepulse inhibition;and (3) decreased response of the cortical pyramidal neurons to NMDA in adulthood, in PICK1 KO mice. Based on preliminary data, our overall hypothesis is that neonatal deficits in D-serine, which is likely to associate with abnormal glutamate function, affect the maturation of prefrontal cortical circuits and result in deficits in synaptic and NMDA-dependent responses in pyramidal neurons and interneurons in adulthood, whereas at this time the levels of D-serine are normal. In Aim 1, we will examine levels of D-serine in the forebrain during development, especially in neonatal stages in PICK1 KO mice. In Aim 2, we will characterize adult PICK1 KO mice by a set of behavioral assays, in particular those for measuring cortical functions, and also by electrophysiological approaches. In Aim 3, we will normalize the levels of D-serine in PICK1 KO mice by administering D-serine, if necessary, combined with a DAAO inhibitor during the neonatal stage. We will then examine whether the D-serine treatment during neonatal periods influences possible abnormal behaviors and physiological phenotypes in adult PICK1 KO mice. Through these experiments, we will study a role for PICK1 in the neonatal forebrain in conjunction with D-serine, hoping that the information obtained from this study will be an important basis in understanding mental disorders and brain development. PUBLIC HEALTH RELEVANCE: PICK1 knockout mice Recent evidence has suggested that PICK1 may regulate glutamate neurotransmission via regulating D-serine metabolism in the neonatal forebrain. Formation of neuronal circuitry during neonatal stages is crucial for proper brain development and functions of adult brain. We will study role for PICK1 in the neonatal forebrain in conjunction with D- serine by characterizing PICK1 knockout mice, hoping that the information obtained from this study will be an important basis in understanding mental disorders and brain development.